Glucocorticoid modification of spinal dopamine receptor activation by apomorphine

380

Brain Research, 267 (1983) 38(~-383 Elsevier Biomedical Press

Glucocorticoidmodifica~n of spinal dopamine receptor activation by apornorphine EDWARD D. HALL* and CARL V. TYLER. Jr.

Program in Pharmacology, Northeastern Ohio Universities, College of Medicine, R ootstown, Ohio 442 72 ( U. S. A. ) (Accepted January I lth, 1983)

Key words: glucocorticoids - apomorphine - dopamine - receptors - spinal cord

The effects of an intensive short-term glucocorticoid (e.g. triamcinolone) regimen in cats have been studied on the actions of the dopamine (DA) receptor agonist apomorphine (APO) on spinal lumbar primary afferent excitability (dorsal root reflex or DRR) and monosynaptic reflex (MSR) transmission. Glucocorticoid dosing significantly decreased the APO-induced depression of the spinal DRR, but not the similar action of APO on the MSR: This complex effect of triamcinolone on spinal dopaminergic activation by APO may represent a differential action ofglucocorticoid on two types of spinal DA receptors with one type, but not the other, undergoing partial desensitization.

Glucocorticoid treatment, particularly in high doses, for a variety of medical conditions has been often associated with psychiatric disturbances ranging in character from mild alterations in mood to schizophrenic episodes 1°. Similarly, patients suffering from the hyper-cortisolism of Cushing's disease commonly display a wide variety of affective and behavioral disorders. Furthermore, many individuals with endogenous depression have elevated plasma levels of cortisoP 2-~3which has been speculated to possibly play a role in the pathophysiology of the affective disorder ~2. A number of investigations in this and other laboratories have attempted to ascertain the central neurochemical and neurophysiological effects of the glucocorticoids in order to elucidate the possible mechanism(s) of the behavioral and psychiatric actions of these hormones. In view of the generally accepted primacy of biogenic amine neurotransmitters in the pathophysiology of the affective disorders~ and schizophrenia ~6, these studies have largely focused on glucocorticoid effects on central biogenic

amines7. For example, recent work in this laboratory has employed the monosynaptic reflex (MSR) pathway of the cat lumbar spinal cord to show that short term intensive treatment with glucocorticoid (e.g. triamcinolone) significantly modifies the descending serotonergic and noradrenergic facilitation of spinal MSR transmission6.L Specifically, triamcinolone treatment has been found to enhance the MSR facilitatory effects of pharmacological serotonergic activation by combined administration 5-hydroxytryptophan and amitriptyline, while at the same time depressing the MSR facilitatory action of noradrenergic receptor stimulation by methoxamine. In addition to the long-recognized presence of the bulbospinal serotonergic and noradrenergic pathways which modulate spinal reflex excitability, more recent investigations have fairly convincingly demonstrated the existence of a descending dopaminergic system that also influences reflex transmission in the spinal c o r d 2.3.4,1~ . Moreover, pharmacological studies have shown that administration of the selective dopaminergic agonist apomorphine (APO) can acutely af-

* To whom all correspondence should be addressed. Current address: CNS Diseases Research Unit, The Upjohn Co., Kalamazoo, M149001, U.S.A.

381 fect reflex transmission TM. Consequently, in the presently reported study, the previous findings of a significant effect of glucocorticoid dosing on spinal biogenic aminergic modulation of spinal M S R transmission 6.7 have been extended to include an analysis of the action of intensive triamcinolone treatment on dopaminergic spinal activation. The effects of APO on the lumbar spinal dorsal root reflex (DRR, i.e. an index of primary afferent excitability) and on MSR transmission is untreated and glucocorticoid treated cats have been determined. Twelve adult cats of either sex (1.8-4.0 kg) were employed in this study. In all cats, a tracheotomy was performed under halothane anesthesia and the spinal cord transected at the C 1 level. Anesthesia was terminated and positive pressure ventilation with room air begun. One carotid artery was cannulated for standard blood pressure recording and both carotids were ligated and the vertebral arteries mechanically compressed to produce brain ischemia. A dorsal laminectomy exposed the spinal cord from L4 to $2 and the L7 and S 1 dorsal and ventral roots were unilaterally sectioned at their points of exit through the spinal column. The animal was then placed in a prone position in a Kopf 1780 spinal unit with the L3 spinous process clamped to help hold the animal in a fixed position. The skin edges of the incision were retracted to form a basin which was filled with mineral oil maintained at 37 °C via radiant heat. Complete neuromuscular paralysis was produced and maintained throughout the experiment with gallamine triethiodide. The distally sectioned L7 dorsal root was split into two bundles of approximately equal diameters. Stimuli were then applied, in all experiments, at a frequency of 0.2 Hz to one dorsal root bundle with bipolar platinum-iridium hook electrodes as square pulses of 0.4 ms duration. One pair of bipolar recording electrodes was then placed on the L7 ventral root and another pair was placed on the other half of the L7 dorsal root. These were used to record the monosynaptic (MSR) and dorsal root (DRR) reflex discharges, respectively. The stimulus intensity was adjusted to 1.2 × the strength required to pro-

duce the maximal MSR. Series of 10 successive MSRs or DRRs were summated on a Tracor Northern 1505 signal averager, the display of which was photographed for later amplitude measurement. Prior to experiment, 6 of the animals were treated with triamcinolone diacetate (Aristocort, Lederle Laboratories, Pearl River, NY) as previously described 6.8,9 in a regimen of 8 m g / k g i.m. (suprascapular muscles) once daily for 7 days. The subsequent experiments were then carried out on the first day after the last triamcinolone dose. The remaining 6 cats were untreated. The effects of APO on the spinal MSR and D R R were examined as described by Schlosser et al. Apomorphine hydrochloride (Sigma Chemicals, St. Louis, MO) was dissolved in 0.9% NaC1 (10 m g / m l ) with gentle warming and administered i.v. (brachial vein) in a dose of 10 m g / k g infused over 5 min. The amplitudes (summation of 10 successive responses) of the MSR and D R R were measured at 5, 10, 20, 30, 40, 50 and 60 min after the beginning of the APO infusion. Apomorphine, in a dose equal to that presently employed, has been shown to produce a depression in both the cat spinal D R R and the MSR 14. As similarly shown in Fig. 1, the 10 m g / k g APO dose produced approximately a 70% decline in both the D R R and the MSR in non-glucocorticoid treated animals. In comparison, the APO infusion caused only about half as much of a decrease in the D R R in the triamcinolone pretreated animals (P ~ 0.005 by repeated measures ANOVA; F = 15.83, df = 1,10). The APO-induced depression in the MSR was also decreased by the glucocorticoid; however, not to a significant degree (F = 0.28, df = 1,9). The 5 min l0 m g / k g APO infusion consistently produced a dramatic rise in blood pressure in both untreated and glucocorticoid treated preparations. However, as also reported by others 14, the pressure effect of APO was short-lived (approx. 15 min) and did not correlate with the prolonged duration of the spinal reflex depression. The present results have demonstrated a significant glucocorticoid modification of spinal

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Fig. 1. Time courseof the effectsofa 5 rain 10 mg/kg i.v. infusion of apomorphine on the amplitude of the cat lumbar spinal dorsal root and monosynapticreflexes(see text for method and statistical comparisons), n = number of animals; data points -- mean amplitude _ S.E.

DA receptor activation. The effects of the direct acting DA receptor agonist APO on reflex excitability are attenuated suggesting a possible depression in DA receptor responsiveness. However, this effect is complex since triamcinolone dosing significantly decreases the DRR depression by APO, but does not affect the APO-induced decrease in the MSR. The present experiments do not allow an exact elucidation of the nature of this depressed dopaminergic responsiveness in the spinal cord ofglucocorticoid-treated animals. However, the simplest explanation for the differential modification of the DRR and MSR actions of APO

centers around the possibility of at least two populations or subtypes of spinal DA receptors as demonstrated in higher CNS areas ~5. Thus, the actions ofglucocorticoid treatment on spinal DA receptor activation might be explainable on the basis that the responsiveness of one type, possibly responsible for the DRR depression by APO H, is blunted by triamcinolone, whereas a different DA receptor, which may mediate the MSR decrease by APO H4, is unaffected. Previously, it has been found that the identical treatment of cats with triamcinolone also blunts the activation of spinal alpha noradrenergic receptors by methoxamine6.i According to the present findings, it would appear that this same decrease in receptor responsiveness by intensive glucocorticoid treatment occurs in some spinal DA receptors but not others. The fact that these two effects are indeed distinct is supported by the reported prevention of the spinal depressant actions of APO by the selective DA receptor antagonists haloperidol t,~z and metaclopramide ~, but not the alpha receptor blocker phenoxybenzamine ~2,or phentolamine ~. In distinct contrast to catecholamine transmission, the functional level of the spinal serotonergic system is concomitantly facilitated by intensive glucocorticoid treatment. This has been demonstrated by a triamcinolone-enhanced increase in the cat spinal MSR in response to combined administration of the serotonin precursor 5-hydroxytryptophan and the selective serotonin reuptake inhibitor amitriptyline6-7. Therefore, it should be noted that the glucocorticoid depression of catecholamine receptor activation is not generalizable to other CNS biogenic amine transmitters. Nevertheless, the demonstrated action of glucocorticoid treatment to modify spinal DA receptor activation, concomitant with a significant effect on spinal alpha noradrenergic and serotonergic function6.7 further shows that central biogenic amine systems are influenced considerably by glucocorticoid. Assuming that these effects, as studied in the cat spinal cord, may at least in part be relevant to effects on biogenic aminergic neurotransmission in higher centers, further investigation may clarify the role of increased glucocorticoid activity in

383 the biogenic amine derangements observed in certain psychiatric disorders. The authors gratefully acknowledge the tech-

nical assistance of Mrs. Brigitte Hirst, the gift of triamcinolone diacetate (Aristocort) from the Lederle Co. of Pearl River, NY and the financial support of NIMH Grant 34111.

1 Carp, J. S. and Anderson, R. J., Dopamine receptor-mediated depression of spinal monosynaptic transmission, Brain Research, 242 (1982) 247-254. 2 Commissiong, J. W., Galli, C. L. and Neff, N. H., Differentiation of dopaminergic and noradrenergic neurons in rat spinal cord, J. Neurochem., 30 (1978) 1095-1099. 3 Commissiong, J. W. and Neff, N. H., Current status of dopamine in the mammalian spinal cord, Biochem. Pharmacol., 28 (1979) 1569-1573. 4 Commissiong, J. W. and Sedgwick, E. M., Modulation of the tonic stretch reflex by monoamines, Europ. J. Pharmacol., 57 (1983) 83-92. 5 Garver, D. L. and Davis, J. M., Biogenic amine hypotheses of affective disorders, Life Sci., 24 (1979) 383-394. 6 Hall, E. D., Glucocorticoid effects on serotonergic and noradrenergic facilitation of spinal monosynaptic transmission, Psychiat. Res., 2 (1980) 241-250. 7 Hall, E. D., Glucocorticoid effects on central nervous excitability and synaptic transmission, Int. Rev. Neurobiol., 23 (1982) 165- 195. 8 Hall, E. D. and Baker, T., Further studies of glucocorticoid effects on spinal cord function: single and repetitive monosynaptic transmission and apparent Ia afferent transmitter turnover, J. Pharmacol. exp. Ther., 210 (1979) !12-115. 9 Hall, E. D., Baker, T. and Riker, W. F., Glucocorticoid

effects on spinal cord function, J. Pharmacol. exp. Ther., 206 (1978) 361-370. Haynes, R. C. and Murad, F., Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs, inhibitors of adrenocortical steroid biosynthesis. In A. G. Gilman, L. S. Goodman and A. Gilman (Eds.), The Pharmacological Basis of Therapeutics, Macmillan, New York, 1980, pp. 1466-1496. Mouchet, P., Guerin, B. and Feuerstein, C., Dissociate destruction of noradrenaline and dopamine descending projections in the thoracic spinal cord of the rat, Life Sci., 30 (1982) 373- 381. Prange, A. J., Lipton, M. A., Nemeroff, C. B. and Wilson, I. C., The role of hormones in depression, Life Sci., 20 (1977) 1305-1318. Sachar, E. J., Asnis, G., Halbreich, U., Nathan, R. S. and Halpern, F., Recent studies in the neuroendocrinology of major depressive disorders, Psych. Clin. North Amer., 3 (1980) 313-326. Schlosser, W., Horst, W. D., Spiegel, H. E. and Sigg, E. G., Apomorphine and its effects on the spinal cord, Neuropharmacology, 11 (1972) 417-426. Seeman, P., Brain dopamine receptors, Pharmacol. Rev., 32 (1981) 229-313. Snyder, S. H., Dopamine receptors, neuroleptics and schizophrenia, A mer. J. Psychiat., 138 ( 1981) 460-464.

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